Pectolinarigenin targeting FGFR3 alleviates osteoarthritis progression by regulating the NF-κB/NLRP3 inflammasome pyroptotic pathway.

OBJECTIVE: Osteoarthritis (OA) is a chronic degenerative disease characterized by cartilage degeneration, involving inflammation, pyroptosis, and degeneration of the extracellular matrix (ECM). Pectolinarigenin (PEC) is a natural flavonoid with antioxidant, anti-inflammatory and anti-tumor properties. This study aims to explore the potential of PEC in ameliorating OA progression and its underlying mechanisms. METHODS: Chondrocytes were exposed to 10 ng/mL IL-1ß to simulate OA-like changes. The effect of PEC on IL-1ß-treated chondrocytes was assessed using ELISA, western blot, and immunofluorescence. The mRNA sequencing (mRNA-seq) was employed to explore the possible targets of PEC in delaying OA progression. The OA mouse model was induced through anterior cruciate ligament transection (ACLT) and divided into sham, ACLT, ACLT+5 mg/kg PEC, and ACLT+10 mg/kg PEC groups. Micro-computed tomography and histological analysis were conducted to confirm the beneficial effects of PEC on OA in vivo. RESULTS: PEC mitigated chondrocyte pyroptosis, as evidenced by reduced levels of pyroptosis-related proteins. Additionally, PEC attenuated IL-1ß-mediated chondrocyte ECM degradation and inflammation. Mechanistically, mRNA-seq showed that FGFR3 was a downstream target of PEC. FGFR3 silencing reversed the beneficial effects of PEC on IL-1ß-exposed chondrocytes. PEC exerted anti-pyroptotic, anti-ECM degradative, and anti-inflammatory effects through upregulating FGFR3 to inhibit the NF-κB/NLRP3 pyroptosis-related pathway. Consistently, in vivo experiments demonstrated the chondroprotective effects of PEC in OA mice. CONCLUSION: PEC alleviate OA progression by FGFR3/NF-κB/NLRP3 pathway mediated chondrocyte pyroptosis, ECM degradation and inflammation, suggesting the potential of PEC as a therapeutic agent for OA.

Decrease in the inflammatory cytokines of LPS-stimulated PBMCs of patients with atherosclerosis by a TLR-4 antagonist in the co-culture with HUVECs.

Toll-like receptors (TLRs) are among the players of inflammation during atherosclerosis. We assessed the effects of Eritoran, a TLR-4 antagonist, on lipopolysaccharide (LPS)-induced cytokines production by Peripheral Blood Mononuclear Cells (PBMCs) of patients with high-stenosis (HS) (n = 6) and healthy controls (HCs) (n = 6) co-cultured with Human Umbilical Vein Endothelial Cells (HUVECs). LPS stimulation significantly increased the levels of IL-6 (P = 0.007 and P = 0.005), TNF-α (P = 0.006 and P = 0.005), IL-2 (P = 0.007 and P = 0.002), IFN-γ (P = 0.006 and P = 0.003), IL-17A (P = 0.004 and P = 0.003), IL-17F (P = 0.005 and P = 0.003), IL-5 (P = 0.007 and P = 0.005), IL-13 (P = 0.006 and P = 0.005), IL-9 (P = 0.005 and P = 0.005) and IL-21 (P = 0.007 and P = 0.005) in HUVECs co-cultured with HC and HS PBMCs as compared with un-stimulated co-culture condition, respectively. Eritoran treatment (50 µg/mL and 100 µg/mL) significantly reduced the levels of LPS-induced IL-6 (P = 0.007 and P = 0.006; P = 0.007 and P = 0.007), TNF-α (P = 0.005 and P = 0.003; P = 0.007 and P = 0.005), IL-2 (P = 0.007 and P = 0.005; P = 0.005 and P = 0.004), IFN-γ (P = 0.007 and P = 0.005; P = 0.005 and P = 0.004), IL-17A (P = 0.005 and P = 0.002; P = 0.005 and P = 0.002), IL-17F (P = 0.006 and P = 0.006; P = 0.005 and P = 0.005), IL-5 (P = 0.007 and P = 0.006; P = 0.007 and P = 0.007), IL-9 (P = 0.005 and P = 0.005; P = 0.005 and P = 0.005) and IL-21 (P = 0.007 and P = 0.007; P = 0.005 and P = 0.005) in stimulated HUVECs co-cultured with HC and HS PBMCs, compared to un-treated condition, respectively. Our results demonstrate that attenuating effect of Eritoran on the inflammatory responses to LPS is higher in PBMCs of patients with high stenosis, suggesting its potential role in ameliorating inflammatory conditions in atherosclerosis.

S100A8 may govern hyper-inflammation in severe COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic threatens human species with mortality rate of roughly 2%. We can hardly predict the time of herd immunity against and end of COVID-19 with or without success of vaccine. One way to overcome the situation is to define what delineates disease severity and serves as a molecular target. The most successful analogy is found in BCR-ABL in chronic myeloid leukemia, which is the golden biomarker, and simultaneously, the most effective molecular target. We hypothesize that S100 calcium-binding protein A8 (S100A8) is one such molecule. The underlying evidence includes accumulating clinical information that S100A8 is upregulated in severe forms of COVID-19, pathological similarities of the affected lungs between COVID-19 and S100A8-induced acute respiratory distress syndrome (ARDS) model, homeostatic inflammation theory in which S100A8 is an endogenous ligand for endotoxin sensor Toll-like receptor 4/Myeloid differentiation protein-2 (TLR4/MD-2) and mediates hyper-inflammation even after elimination of endotoxin-producing extrinsic pathogens, analogous findings between COVID-19-associated ARDS and pre-metastatic lungs such as S100A8 upregulation, pulmonary recruitment of myeloid cells, increased vascular permeability, and activation coagulation cascade. A successful treatment in an animal COVID-19 model is given with a reagent capable of abrogating interaction between S100A8/S100A9 and TLR4. In this paper, we try to verify our hypothesis that S100A8 governs COVID-19-associated ARDS.

Safety and Efficacy of Intravenous Ferric Derisomaltose Compared to Iron Sucrose for Iron Deficiency Anemia in Patients with Chronic Kidney Disease With and Without Heart Failure.

Ferric derisomaltose (FDI) is an intravenous (IV) high-dose iron formulation approved in the US for the treatment of iron deficiency anemia in adults who are intolerant of/have had an unsatisfactory response to oral iron, or who have non-dialysis-dependent chronic kidney disease (NDD-CKD). FERWON-NEPHRO was a randomized, open-label, multicenter clinical trial evaluating the safety and efficacy of a single infusion of FDI 1,000 mg versus up to 5 doses of iron sucrose (IS) 200 mg (recommended cumulative dose, 1,000 mg) over 8 weeks in patients with NDD-CKD and iron deficiency anemia. Of 1,525 patients included in the safety analysis, 244 (16%) had a history of heart failure (HF). Overall, the rate of serious or severe hypersensitivity reactions was low and did not differ between treatment groups. Cardiovascular adverse events (AEs) were reported for 9.4% of patients who had HF and 4.2% who did not. Time to first cardiovascular AE was longer following administration of FDI compared with IS (hazard ratio: 0.59 [95% CI: 0.37, 0.92]; p=0.0185), a difference that was similar in patients with or without HF (p=0.908 for interaction). Patients achieved a faster hematological response (assessed by changes in hemoglobin and ferritin concentrations, and increase in transferrin saturation) with FDI versus IS. In conclusion, in patients with NDD-CKD, a single infusion of FDI was safe, well tolerated, and was associated with fewer cardiovascular AEs and a faster hematological response, compared to multiple doses of IS. These effects were similar for patients with and without HF.

Association between intravenous iron therapy and short-term mortality risk in older patients undergoing hip fracture surgery: an observational study.

BACKGROUND: Anemia is common among ortho-geriatric hip fracture patients and is associated with prolonged recovery and increased postoperative mortality rate. Intravenous iron seems to increase hemoglobin recovery and reduce the mortality rate in patients undergoing orthopedic surgeries. This study investigated the association between short-term mortality risk and intravenous iron therapy in older patients undergoing hip fracture surgery. METHODS: This observational study included 210 patients undergoing hip fracture surgery from July 2018 to May 2020. These 210 patients were alive and had a hemoglobin ≤ 6.5 mmol/L on the 3rd postoperative day. In May 2019, a local intravenous iron therapy protocol was implemented and recommended intravenous iron (Monofer©) if hemoglobin on the 3rd postoperative day was ≤ 6.5 mmol/L. According to the treatment of postoperative anemia between the 1st and 3rd day post-surgery, the patients were divided into four groups: no treatment (n=52), blood transfusion (n=38), IV Monofer (n=80), and blood transfusion and IV Monofer (n=40). Primary outcome was 30-day mortality post-surgery. The secondary outcome was the impact on hemoglobin level 14-30 days postoperatively. Multivariable Cox regression was used to estimate the 30-day mortality standardized for covariates. RESULTS: Of 210 patients, 17 (8.1%) died within 30 days after surgery. There was a significantly lower mortality among the patients who received IV Monofer compared to those who received no treatment (HR 0.17, 95% CI [0.03-0.93], P = 0.041). Among the 86 patients with available hemoglobin measurements within 14 to 30 days post-surgery, there was no significant difference in hemoglobin level between the various treatment groups (mean 6.6 mmol/L, P = 0.1165). CONCLUSION: IV Monofer on the 3rd postoperative day in older hip fracture patients seemed to reduce 30-day mortality compared with no treatment. No significant differences in hemoglobin levels between 14 and 30 days post-surgery across treatment groups were found, although this was assessed in a subset of patients with available hemoglobin levels warranting further study.

Intravenous ferric derisomaltose for the treatment of iron deficiency anemia.

Intravenous (IV) iron is the therapy of choice when oral iron is ineffective or poorly tolerated, yet use has been limited by fears of hypersensitivity reactions (HSRs). Newer formulations that bind iron more tightly and release it more slowly have made the risk of serious or severe HSRs very low. One such formulation, ferric derisomaltose, has been approved in the United States for delivery of 1000 mg iron in a single IV infusion. Ferric derisomaltose rapidly repletes iron parameters with low rates of serious or severe HSRs. Single-infusion iron repletion offers convenience, eliminates adherence concerns, and reduces healthcare resource utilization.

NIMO-CKD-UK: a real-world, observational study of iron isomaltoside in patients with iron deficiency anaemia and chronic kidney disease.

BACKGROUND: Intravenous iron is often used to treat iron deficiency anaemia in non-dialysis chronic kidney disease (ND-CKD), but the optimal dosing regimen remains unclear. We evaluated the impact of high- versus low-dose intravenous iron isomaltoside on the probability of retreatment with intravenous iron in iron-deficient ND-CKD patients. METHODS: This real-world, prospective, observational study collected data from 256 ND-CKD patients treated for anaemia in the UK. Following an initial course of iron isomaltoside, patients were followed for ≥12 months. Iron dose and the need for retreatment were determined at the investigators' discretion. The primary study outcome was the need for retreatment at 52 weeks compared between patients who received >1000 mg of iron during Course 1 and those who received ≤1000 mg. Safety was evaluated through adverse drug reactions. RESULTS: The probability of retreatment at Week 52 was significantly lower in the >1000 mg iron group (n = 58) versus the ≤1000 mg group (n = 198); hazard ratio (95% confidence interval [CI]): 0.46 (0.20, 0.91); p = 0.012. Mean (95% CI) haemoglobin increased by 6.58 (4.94, 8.21) g/L in the ≤1000 mg group and by 10.59 (7.52, 13.66) g/L in the >1000 mg group (p = 0.024). Changes in other blood and iron parameters were not significantly different between the two groups. Administering >1000 mg of iron isomaltoside saved 8.6 appointments per 100 patients compared to ≤1000 mg. No serious adverse drug reactions were reported. Of the patients who received ≤1000 mg of iron in this study, 82.3% were eligible for a dose >1000 mg. CONCLUSIONS: The >1000 mg iron isomaltoside regimen reduced the probability of retreatment, achieved a greater haemoglobin response irrespective of erythropoiesis-stimulating agent treatment, and reduced the total number of appointments required, compared to the ≤1000 mg regimen. Many of the patients who received ≤1000 mg of iron were eligible for >1000 mg, indicating that there was considerable underdosing in this study. TRIAL REGISTRATION: ClinicalTrials.gov NCT02546154 , 10 September 2015.

Conversion of haemodialysis patients from iron sucrose to iron isomaltoside: a real-world experience.

BACKGROUND: Anaemia is common in haemodialysis (HD) patients and associated with significant morbidity and mortality. Intravenous (IV) iron combined with erythropoiesis-stimulating agents (ESA) is the mainstay treatment of anaemia in these patients. The comparative efficacy and risk of adverse events with IV iron preparations have been assessed in only a few trials. METHODS: This was a retrospective observational study in 2 centres designed to compare the safety and efficacy of iron sucrose (IS-Venofer®) versus iron isomaltoside (IIM-Diafer®) in haemodialysis patients. The study included patients currently on dialysis and receiving Venofer who were switched to Diafer® and monitored for at least 12 months for each iron preparation. RESULTS: A total of 190 patients were included and had a mean age of 65.8 years (SD ± 15.5). Non-inferiority was confirmed with no change in mean haemoglobin per mg of iron administered over a 12-month period. In total there were 41,295 prescriptions of iron isomaltoside and 14,685 of iron sucrose with no difference in the number of reported adverse events during the study period (7 each, none were severe). There was a statistically significant effect on Hb over time after conversion, including adjustment for multiple comparisons. There were significant improvements in ferritin over time, which remained at 6 months (P < 0.01). The weekly iron dose was similar after adjustment (P = 0.02). The EPO dose did not differ significantly after month 0 in patients switched to IIM. CONCLUSIONS: This study demonstrates the comparative safety and efficacy of iron isomaltoside versus iron sucrose, with similar dosing schedules in dialysis patients. Iron isomaltoside is non-inferior to iron sucrose in maintaining Hb in patients on regular haemodialysis/haemodiafiltration with no difference in the number of reported adverse events.

Intralymphatic histiocytosis in healing cellulitis: Case report and review of the literature.

Intralymphatic histiocytosis (ILH) is a rare skin benign condition observed in a variety of inflammatory settings. It is characterized by the presence of ectatic dermal lymphatic vessels containing aggregates of histiocytes. Associated conditions that have been identified include rheumatoid arthritis, metallic orthopedic implants, inflammatory bowel disease, and malignancies of the breast, skin, and colon. Some cases with no attributable underlying cause have been described. The pathophysiology of ILH is not well understood. It has been proposed that it may represent macrophage migration during immune activation. Herein, we present the first description of ILH observed in the healing phase of cellulitis on the skin of the breast. Awareness of this possibility is important when the diagnosis of intravascular carcinomatosis is being considered.

Safety of intravenous iron isomaltoside for iron deficiency and iron deficiency anemia in pregnancy.

PURPOSE: To evaluate the efficacy and safety for mother and child of using intravenous iron isomaltoside (IV-IIM) during pregnancy. METHODS: Using an appointment register, we retrospectively identified all pregnant women who received a single dose of 1000 or 1500 mg IV-IIM in the maternity ward of Falu Hospital and subsequently gave birth between August 6, 2013 and July 31, 2018. Women who received IV-IIM (case group) were individually matched with pregnant women who did not receive IV-IIM (control group) by delivery date, maternal age (± 2 years), and parity. Adverse drug reactions (ADRs), demographic characteristics, hemoglobin and s-ferritin counts, pregnancy and delivery complications, and infant data (APGAR score, pH at umbilical artery, birthweight, birth length, intrauterine growth restriction and neonatal ward admission). Data were obtained from electronic patient charts. SPSS was used for descriptive statistics. RESULTS: During the 5-year period, 213 women each received a single administration of IV-IIM. Ten (4.7%) ADRs occurred during IV-IIM administration. All ADRs were mild hypersensitivity reactions, abated spontaneously within a few minutes, and did not recur on rechallenge. No association between IIM dose and ADR frequency was noted. Maternal and fetal outcomes, including hemoglobin counts at delivery and postpartum, were similar in the case and control groups. CONCLUSION: These results support the convenience, safety, and efficacy of a single high-dose (up to 1500 mg) infusion of IV-IIM for iron deficiency or iron deficiency anemia during pregnancy.

Development of a Resource Impact Model for Clinics Treating Pre-Operative Iron Deficiency Anemia in Ireland.

INTRODUCTION: Intravenous (IV) iron is typically the preferred treatment for patients with iron deficiency anemia (IDA) who cannot tolerate or absorb oral iron, or who require fast replenishment of iron stores pre-operatively. Several IV iron formulations are available with different dosing characteristics affecting infusion speed and maximum dose. The aim was to develop a resource impact model to calculate the cost of establishing an IV iron clinic and model resource impact of different IV irons to inform clinicians and service providers implementing innovative pre-operative IV iron services in Ireland. METHODS: A resource impact tool was developed to model resource utilization and IDA treatment costs. Two fast-administration, high-dose formulations of IV iron are available in Ireland: iron isomaltoside 1000/ferric derisomaltose (IIM) and ferric carboxymaltose (FCM). The tool modeled clinic throughput based on their different dosing characteristics in a specific IDA population, capturing fixed overheads, variable costs, clinic income from private and publicly-funded patients, and savings associated with IV iron. RESULTS: Based on a 70:30 split between public and private patients in a new pre-operative service with capacity for 12 infusion slots weekly, IIM would facilitate correction of iron deficits in 474 patients annually, resulting in a net annual clinic balance of €42,736 on income of €159,887 and net costs of €117,151. FCM would facilitate treatment of 353 patients, resulting in a net annual clinic balance of €36,327 on income of €116,050 and costs of €79,722, a difference of €6408 and 121 patients treated in favor of using IIM over FCM. CONCLUSION: Based on this provider-perspective analysis, IIM would maximize clinic throughput relative to other IV iron formulations, allowing clinicians in Ireland to optimize their current service provision and expenditure, and model the impact of introducing IV iron clinics for pre-operative patients with IDA.

Effects of Iron Isomaltoside vs Ferric Carboxymaltose on Hypophosphatemia in Iron-Deficiency Anemia: Two Randomized Clinical Trials.

Importance: Intravenous iron enables rapid correction of iron-deficiency anemia, but certain formulations induce fibroblast growth factor 23-mediated hypophosphatemia. Objective: To compare risks of hypophosphatemia and effects on biomarkers of mineral and bone homeostasis of intravenous iron isomaltoside (now known as ferric derisomaltose) vs ferric carboxymaltose. Design, Setting, and Participants: Between October 2017 and June 2018, 245 patients aged 18 years and older with iron-deficiency anemia (hemoglobin level ≤11 g/dL; serum ferritin level ≤100 ng/mL) and intolerance or unresponsiveness to 1 month or more of oral iron were recruited from 30 outpatient clinic sites in the United States into 2 identically designed, open-label, randomized clinical trials. Patients with reduced kidney function were excluded. Serum phosphate and 12 additional biomarkers of mineral and bone homeostasis were measured on days 0, 1, 7, 8, 14, 21, and 35. The date of final follow-up was June 19, 2018, for trial A and May 29, 2018, for trial B. Interventions: Intravenous administration of iron isomaltoside, 1000 mg, on day 0 or ferric carboxymaltose, 750 mg, infused on days 0 and 7. Main Outcomes and Measures: The primary end point was the incidence of hypophosphatemia (serum phosphate level <2.0 mg/dL) between baseline and day 35. Results: In trial A, 123 patients were randomized (mean [SD] age, 45.1 [11.0] years; 95.9% women), including 62 to iron isomaltoside and 61 to ferric carboxymaltose; 95.1% completed the trial. In trial B, 122 patients were randomized (mean [SD] age, 42.6 [12.2] years; 94.1% women), including 61 to iron isomaltoside and 61 to ferric carboxymaltose; 93.4% completed the trial. The incidence of hypophosphatemia was significantly lower following iron isomaltoside vs ferric carboxymaltose (trial A: 7.9% vs 75.0% [adjusted rate difference, -67.0% {95% CI, -77.4% to -51.5%}], P < .001; trial B: 8.1% vs 73.7% [adjusted rate difference, -65.8% {95% CI, -76.6% to -49.8%}], P < .001). Beyond hypophosphatemia and increased parathyroid hormone, the most common adverse drug reactions (No./total No.) were nausea (iron isomaltoside: 1/125; ferric carboxymaltose: 8/117) and headache (iron isomaltoside: 4/125; ferric carboxymaltose: 5/117). Conclusions and Relevance: In 2 randomized trials of patients with iron-deficiency anemia who were intolerant of or unresponsive to oral iron, iron isomaltoside (now called ferric derisomaltose), compared with ferric carboxymaltose, resulted in lower incidence of hypophosphatemia over 35 days. However, further research is needed to determine the clinical importance of this difference. Trial Registration: ClinicalTrials.gov Identifiers: NCT03238911 and NCT03237065.

Indirect methods of comparison of the safety of ferric derisomaltose, iron sucrose and ferric carboxymaltose in the treatment of iron deficiency anemia.

Objectives: The benefits of intravenous (IV) iron greatly outweigh the risks, but IV iron formulations carry a small risk of hypersensitivity reactions (HSRs). The objective was to use standardized Medical Dictionary for Regulatory Activities queries (SMQs) to compare the safety of ferric derisomaltose/iron isomaltoside 1000 (FDI), iron sucrose (IS), and ferric carboxymaltose (FCM) using prospective trial data.Methods: Prospective trials reporting the incidence of SMQ-coded serious or severe HSRs were identified in the literature. Four SMQs were used: narrow hypersensitivity terms (A), and broad terms pertaining to potential respiratory HSRs (B), skin HSRs (C), and cardiovascular HSRs (D). Bayesian inference, naïve pooling, and adjusted indirect approaches were employed to compare HSR incidence.Results: Twenty one prospective trials including over 8,000 patients receiving FDI, FCM or IS were retrieved. Odds ratios of any serious or severe HSR (all groups) with FDI relative to FCM were 0.41, 0.39, and 0.45 according to the Bayesian, naïve and adjusted approaches, respectively.Conclusions: The risk of serious or severe HSRs was lower with FDI relative to FCM and IS. Using data from prospective trials including over 8,000 patients coded using a well-defined standard (SMQs) enabled a robust comparison of HSR incidence between the iron formulations.

Maltobionic acid accelerates recovery from iron deficiency-induced anemia in rats.

In experiments 1 and 2, effect of ingestion of maltobionic acid calcium salt (MBCa) on recovery of rats from a latent iron deficiency and from iron deficiency anemia was examined, respectively. After grouping rats into control and iron-deficiency groups, a latent iron deficiency or iron-deficiency anemia was induced in the latter group. And recovery from these states by MBCa containing diets (0%, 3%, and 6% MBCa in diet, classified into MBCa-0, MBCa-3, and MBCa-6 groups) was compared for convalescence period in light of iron sufficient control group. In experiment 1, MBCa ingestion significantly increased the iron concentration in the serum and liver, and promoted recovery from a latent iron deficiency. In experiment 2, hemoglobin and hematocrit levels increased significantly with MBCa intake, and recovery from iron-deficiency anemia was promoted. MBCa effectively promoted the recovery of rats from a subclinical iron deficiency and iron-deficiency anemia.Abbreviations: ANOVA: analysis of variance; DMT1: divalent metal transporter 1; EDTA-2Na: disodium salt of ethylenediaminetetraacetic acid; Fpn: feroportin; Hb: hemoglobin; Ht: hematocrit; ICP-OES: inductivity coupled plasma optical emission spectrometer; MBCa: maltobionic acid calcium salt; nitroso-PSAP: 2-nitroso-5-[N-n-propyl-N-(3-sulfopropyl)amino]phenol; SE: standard error; SI: serum-iron concentration; TSAT: transferrin saturation; TIBC: total iron-binding capacity; UIBC: unsaturated iron-binding capacity.

Low FODMAPs diet for functional abdominal pain disorders in children: critical review of current knowledge / Dieta com baixo teor de FODMAPs para distúrbios de dor abdominal funcional em crianças: revisão crítica do conhecimento atual

ABSTRACT Objective: This narrative review aimed to provide practitioners a synthesis of the current knowledge on the role of a low Fermentable Oligosaccharides Disaccharides Monosaccharides and Polyols diet in reducing symptoms associated with functional abdominal pain disorders in children. This review is focused on the pathophysiology, efficacy and criticism of low Fermentable Oligosaccharides Disaccharides Monosaccharides and Polyols diet in children. Sources: Cochrane Database, Pubmed and Embase were searched using specific terms for Fermentable Oligosaccharides Disaccharides Monosaccharides and Polyols diet interventions and functional abdominal pain disorders. Summary of the findings: In children, only one Randomized Control Trial and one open-label study reported positive results of low Fermentable Oligosaccharides Disaccharides Monosaccharides and Polyols diet; one Randomized Control Trial showed exacerbation of symptoms with fructans in children with Irritable Bowel Syndrome; no effect was found for the lactose-free diet whilst fructose-restricted diets were effective in 5/6 studies. Conclusions: In children there are few trials evaluating low Fermentable Oligosaccharides Disaccharides Monosaccharides and Polyols in functional abdominal pain disorders, with encouraging data on the therapeutic efficacy particularly of fructose-restricted diet. Additional efforts are still needed to fill this research gap and clarify the most efficient way for tailoring dietary restrictions based on the patient's tolerance and/or identification of potential biomarkers of low Fermentable Oligosaccharides Disaccharides Monosaccharides and Polyols efficacy, to maintain nutritional adequacy and to simplify the adherence to diet by labeling Fermentable Oligosaccharides Disaccharides Monosaccharides and Polyols content in commercial products.

RESUMO Objetivo: Nos últimos anos, foram feitos esforços consideráveis para esclarecer o papel da dieta com baixo teor de oligossacarídeos fermentáveis, dissacarídeos, monossacarídeos e polióis (FODMAPs) para o tratamento de distúrbios gastrintestinais funcionais (DGIFs). Esta revisão narrativa teve como objetivo fornecer aos profissionais uma síntese do conhecimento atual sobre o papel de uma dieta com baixo teor de FODMAPs (BFM) na redução dos sintomas associados a distúrbios funcionais de dor abdominal (DFDA) em crianças. Esta revisão está focada na fisiopatologia, eficácia e crítica da dieta BFM em crianças. Fontes: O banco de dados Cochrane, Pubmed e Embase foram pesquisados com o uso dos termos específicos para intervenções na dieta FODMAP e DFDA. Resumo dos achados: Em crianças, apenas um estudo controlado randomizado e um estudo aberto relataram resultados positivos da dieta BFM; um estudo controlado randomizado mostrou exacerbação dos sintomas com frutanos em crianças com síndrome do intestino irritável; nenhum efeito foi encontrado para a dieta livre de lactose, enquanto dietas com restrição de frutose foram eficazes em 5/6 estudos. Conclusões: Existem poucos estudos que avaliam BFM em DFDA em crianças, com dados encorajadores sobre a eficácia terapêutica, particularmente de dietas com restrição de frutose. Esforços adicionais ainda são necessários para preencher essa lacuna de pesquisa e esclarecer a maneira mais eficiente de adaptar as restrições dietéticas com base na tolerância do paciente e/ou identificação de biomarcadores potenciais de eficácia da BFM, para manter a adequação nutricional e simplificar a adesão à dieta, ao incluir informações sobre conteúdo de FODMAPs em rótulos de produtos comerciais.

MytiLec-1 Shows Glycan-Dependent Toxicity against Brine Shrimp Artemia and Induces Apoptotic Death of Ehrlich Ascites Carcinoma Cells In Vivo.

MytiLec-1, a 17 kDa lectin with ß-trefoil folding that was isolated from the Mediterranean mussel (Mytilus galloprovincialis) bound to the disaccharide melibiose, Galα(1,6) Glc, and the trisaccharide globotriose, Galα(1,4) Galß(1,4) Glc. Toxicity of the lectin was found to be low with an LC50 value of 384.53 µg/mL, determined using the Artemia nauplii lethality assay. A fluorescence assay was carried out to evaluate the glycan-dependent binding of MytiLec-1 to Artemia nauplii. The lectin strongly agglutinated Ehrlich ascites carcinoma (EAC) cells cultured in vivo in Swiss albino mice. When injected intraperitoneally to the mice at doses of 1.0 mg/kg/day and 2.0 mg/kg/day for five consecutive days, MytiLec-1 inhibited 27.62% and 48.57% of cancer cell growth, respectively. Antiproliferative activity of the lectin against U937 and HeLa cells was studied by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in vitro in RPMI-1640 medium. MytiLec-1 internalized into U937 cells and 50 µg/mL of the lectin inhibited their growth of to 62.70% whereas 53.59% cell growth inhibition was observed against EAC cells when incubated for 24 h. Cell morphological study and expression of apoptosis-related genes (p53, Bax, Bcl-X, and NF-κB) showed that the lectin possibly triggered apoptosis in these cells.

Immuno-modulating properties of Tulathromycin in porcine monocyte-derived macrophages infected with porcine reproductive and respiratory syndrome virus.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a positive-stranded RNA virus that grows in macrophages and causes acute pneumonia in pigs. PRRSV causes devastating losses to the porcine industry. However, due to its high antigenic variability and poorly understood immunopathogenesis, there is currently no effective vaccine or treatment to control PRRSV infection. The common occurrence of PRRSV infection with bacterial infections as well as its inflammatory-driven pathobiology raises the question of the value of antibiotics with immunomodulating properties for the treatment of the disease it causes. The macrolide antibiotic Tulathromycin (TUL) has been found to exhibit potent anti-inflammatory and immunomodulating properties in cattle and pigs. The aim of this study was to characterize the anti-viral and immunomodulating properties of TUL in PRRSV-infected porcine macrophages. Our findings indicate that blood monocyte-derived macrophages are readily infected by PRRSV and can be used as an effective cellular model to study PRRSV pathogenesis. TUL did not change intracellular or extracellular viral titers, not did it alter viral receptors (CD163 and CD169) expression on porcine macrophages. In contrast, TUL exhibited potent immunomodulating properties, which therefore occurred in the absence of any direct antiviral effects against PRRSV. TUL had an additive effect with PRRSV on the induction of macrophage apoptosis, and inhibited virus-induced necrosis. TUL significantly attenuated PRRSV-induced macrophage pro-inflammatory signaling (CXCL-8 and mitochondrial ROS production) and prevented PRRSV inhibition of non-opsonized and opsonized phagocytic function. Together, these data demonstrate that TUL inhibits PRRSV-induced inflammatory responses in porcine macrophages and protects against the phagocytic impairment caused by the virus. Research in live pigs is warranted to assess the potential clinical benefits of this antibiotic in the context of virally induced inflammation and tissue injury.

Incidence of hypophosphatemia in patients with inflammatory bowel disease treated with ferric carboxymaltose or iron isomaltoside.

BACKGROUND: Iron deficiency and iron deficiency anaemia are common complications in inflammatory bowel disease (IBD). In patients with moderate-to-severe anaemia, oral iron intolerance or ineffectiveness of oral iron, ferric carboxymaltose and iron isomaltoside are widely used. Hypophosphatemia is a side effect of both preparations. AIMS: To investigate the occurrence of hypophosphatemia in IBD patients with iron deficiency/iron deficiency anaemia treated with high-dose intravenous iron. METHODS: A prospective observational study of adult IBD patients with iron deficiency/iron deficiency anaemia was conducted at two study sites where patients received 1000 mg of ferric carboxymaltose or iron isomaltoside. At baseline, weeks 2 and 6, blood and faecal samples were collected. The primary endpoint was to determine the incidence of moderate-to-severe hypophosphatemia. Secondary endpoints included the total incidence of hypophosphatemia, possible risk factors for hypophosphatemia, and response to single-dose intravenous iron. RESULTS: One hundred and thirty patients were included. In the per-protocol set, 52 patients received ferric carboxymaltose and 54 patients received iron isomaltoside. Ferric carboxymaltose treatment had a significantly higher incidence of moderate-to-severe hypophosphatemia compared with iron isomaltoside at week 2 (56.9% vs 5.7%, P < 0.001) and a higher incidence at week 6 (13.7% vs 1.9%, P = 0.054).The overall incidence of hypophosphatemia was significantly higher with ferric carboxymaltose compared with iron isomaltoside treatment at weeks 2 (72.5% vs 11.3%, P < 0.001) and 6 (21.6% vs 3.7%, P = 0.013). CONCLUSIONS: In IBD patients with iron deficiency/iron deficiency anaemia, ferric carboxymaltose was associated with higher incidence, severity and persistence of hypophosphatemia compared with iron isomaltoside. The presence of moderate-to-severe hypophosphatemia beyond 6 weeks is a clinical concern that requires further investigation.

Effects of experimentally induced respiratory disease on the pharmacokinetics and tissue residues of tulathromycin in meat goats.

Tulathromycin is a macrolide antibiotic commonly used for the treatment of respiratory disease in food animal species including goats. Recent research in pigs has suggested that the presence of disease could alter the pharmacokinetics of tulathromycin in animals with respiratory disease. The objectives of this study were (a) compare the plasma pharmacokinetics of tulathromycin in healthy goats as well as goats with an induced respiratory disease; and (b) to compare the tissue residue concentrations of tulathromycin marker in both groups. For this trial, disease was induced with Pasteurella multocida. Following disease induction, tulathromycin was administered. Samples of plasma were collected at various time points up to 312 hr posttreatment, when study animals were euthanized and tissue samples were collected. For PK parameters in plasma, Vz (control: 28.7 ± 11.9 ml/kg; experimental: 57.8 ± 26.6 ml/kg) was significantly higher (p = 0.0454) in the experimental group than the control group, and nonsignificant differences were noted in other parameters. Among time points significantly lower plasma concentrations were noted in the experimental group at 168 hr (p = 0.023), 216 hr (p = 0.036), 264 hr (p = 0.0017), 288 hr (p = 0.0433), and 312 hr (p = 0.0486). None of the goats had tissue residues above the US bovine limit of 5 µg/g at the end of the study. No differences were observed between muscle, liver, or fat concentrations. A significantly lower concentration (p = 0.0095) was noted in the kidneys of experimental goats when compared to the control group. These results suggest that the effect of respiratory disease on the pharmacokinetics and tissue residues appear minimal after experimental P. multocida infection, however as evidenced by the disparity in Cmax , significant differences in plasma concentrations at terminal time points, as well as the differences in kidney concentrations, there is the potential for alterations in diseased versus clinical animals.